Substituted biphenyl acetic acids and ester derivatives thereof

ABSTRACT

New 4(and 5)-substituted phenylacetic acids useful as antiinflammatory, analgesic and anti-pyretic agents.

United States Patent Shen et al. [451 June 20, 1972 54] SUBSTITUTEDBIPHENYL ACETIC [56] References Cited ACIDS AND ESTER DERIVATIVESTHEREOF UNITED STATES PATENTS 3,457,300 7/1969 Dorn et al. ..260/520 xTsung-Ying Shen, Westfield; Conrad P. Dom, Jr., Plainfield, both of NJ.

Assignee: Merck & Co., Inc., Rahway, NJ.

Filed: Dec. 22, 1969 Appl. No.: 887,416

Inventors:

US. Cl. ..260/520, 260/247.7 A, 260/268 BC, 260/286 R, 260/293.76,260/448 R, 260/473 S, 260/473 R, 260/479 K, 260/50l.l, 260/50l.12,

260/50l.l7, 260/515 A, 260/546, 260/559 D, 260/544 M, 260/566 D,260/519, 260/326.3,

260/612 R, 260/613 R, 260/623 R, 260/646,

Int. Cl ..C07c 65/14 Field of Search ..260/520, 473 R, 473 S, 479 RFOREIGN PATENTS OR APPLICATIONS OTHER PUBLICATIONS Roberts et al., BasicPrinciples of Organic Chemistry," W. A. Benjamin Inc., N.Y., NY. (1965)p. 556, 694

France [5 7] ABSTRACT New 4(and 5 )-substituted phenylacetic acidsuseful as anti-inflammatory, analgesic and anti-pyretic agents.

4 Claims, No Drawings SUBSTITUTED BIPI'IENYL ACETIC ACIDS AND ESTERDERIVATIVES THEREOF This invention relates to new biphenyl compounds, toa method of treating inflammation using these compounds and to processesfor producing the same. More specifically, this invention relates tosubstituted 4(or )-(phenyl)-phenylacetic acids, esters, amides,anhydrides and non-toxic pharmaceutically acceptable salts thereof.Still more specifically, this invention relates to compounds having thefollowing formula:

wherein:

X 15) is halogen (chloro, bromo, fluoro and iodo);

R is selected from the group consisting of hydrogen, halogen (chloro,bromo, and fluoro), lower alkyl (such as methyl, ethyl, butyl, pentyl,and the like), and lower alkoxy (such as methoxy, ethoxy, butoxy, andthe like);

R, is selected from the group consisting of hydroxy, amino, lower alkoxy(such as methoxy, ethoxy, butoxy, pentoxy, and the like), loweralkylamino (methylamino, propylamino, pentylamino, and the like),di(lower alkyl)amino (dimethylamino, dibutylamino, propylpentylamino,and the like), diloweralkylaminoloweralkylamino,dloweralkylaminoloweralkoxy, hydroxyloweralkoxy, (3-hydroxypropoxy,2-hydroxypropoxy, 4- hydroxybutoxy and the like), polyhydroxyloweralkoxy(2,3-dihydroxypropoxy, 2,3,4,5,G-pentahydroxyhexyloxy and the like),loweralkoxyloweralkoxy (ethoxyethoxy), phenyl-loweralkoxy (benzyloxy,phenethoxy and the like), phenoxy, substituted phenoxy (such asloweralkoxy, diloweralkylamino, loweralkanoylamino, benzyloxy-Z-carboxy-4-(4'-fluorophenyl), loweralkanolyaminoloweralkoxy, hydrazino,(hydroxylamino), N- morpholino,N-(4-loweralkyl-piperidino)-N-[4-(hydroxyloweralkyl)-piperidino],(hydroxyloweralkyl)amino and a naturally occurring amino acid radicalwith attachment at the N, such as glycine, phenylalanine, proline,methionine and taurine;

R is selected from the group consisting of hydrogen, lower alkyl (suchas methyl, ethyl, butyl, pentyl, and the like), lower alkanoyl (such asacetyl, propionyl, butyryl, and the like), and lower alkenyl (such asallyl, butenyl, and the like); and

R is selected from the group consisting of hydrogen, 3-

lower alkenyl, 3- and 4-lower alkyl, lower alkoxy, benzyl and halo; thepharrnaceutically non-toxic salts of the acid [such as the ammonium,alkali (Na,K) and alkali earth (Ca,Ba,Mg), amine, aluminum, iron,choline, glucosamine, and S-methyl methionine salts, piperazine,diloweralkylaminoloweralkanol, chloroquine, hydroxychloroquine and thelike]; the anhydride of said acids and the mixed anhydrides of saidacids and Z-acetoxy phenyl acetic acid.

In the more preferred aspects of this invention, is hydrogen or loweralkyl, particularly, methyl or lower alkoxy, particularly methoxy;

R, is hydroxy or amino, particularly hydroxy;

R is hydrogen or lower alkanoyl, particularly acetyl;

R, is hydrogen or lower alkyl;

X is chloro or fluoro, particularly fluoro and is on the 4- position ofthe phenyl moiety.

Representative compounds of this invention are:

2-hydroxy-4(or 5 )-(4'-fluorophenyl)-phenylacetamide;

2-hydroxy-4(or 5 )-(4'-fluorophenyl)-3-methylphenylacetamide;

2-acetoxy-4(or 5 4 -fluorophenyl )-phenylacetamide;

2-acetoxy-4(or 5)-(4'-fluorophenyl)-phenylacetmorpholide;

2-hydroxy-4(or 5 4 '-fluoro-2 '-methoxyphenyl )-phenylacetic acid;

2-acetoxy-4(or 5 4 '-fluoro-2 '-methoxyphenyl)-phenylacetic acid;

2-hydroxy-4( or 5 )-(4-fluoro-2'-methylphenyl)-phenylacetic acid;

2-acetoxy-4(or 5 )-(4'-fluoro-3 'methylphenyl)-phenylacetic acid;

2-hydroxy-3-allyl-4(or 5 )-(4'-fluorophenyl)-phenylacetic acid; and

2-hydroxy-3-propyl-4(or 5)-(4'-fluorophenyl)-phenylacetic acid.

This invention also relates to a method of treating inflammation inpatients using a compound of formula I, particularly an especiallypreferred compound as the active constituent.

The compounds of the instant invention can be used to reduceinflammation and relieve pain in such diseases as rheumatoid arthritis,osteoarthritis, gout, infectious arthritis and rheumatic fever.Furthermore, the compounds of the instant invention have better potencyat the same dosage levels than similar type compounds known in the priorart and exhibit a lower incidence of side effects.

The compounds of formula I also have antipyretic and analgesic activityand would be administered and used in the same manner and in the samedosage ranges as if they were being used to treat inflammation asdiscussed further on.

The treatment of inflammation in accordance with the method of thepresent invention is accomplished by orally, parenterally, topically orrectally administering to patients (animal or human) a composition of acompound of formula I, particularly the especially preferred compoundsin a non-toxic pharrnaceutically acceptable carrier, preferably intablet or capsule form.

The non-toxic pharmaceutical carrier may be, for example, either a solidor a liquid. Exemplary of solid carriers are lactose, corn starch,gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba,sucrose, agar, pectin, cab-o-sil, and

acacia. Exemplary of liquid carriers are peanut oil, olive oil, sesameoil and water. Similarly, the carrier or diluent may include a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax.

Several pharmaceutical forms of the therapeutically useful compositionscan be used. For example, if a solid carrier is used, the compositionsmay take the form of tablets, capsules, powders, troches or lozenges,prepared by standard pharmaceutical techniques. If a liquid carrier isused, the preparation may be in the form of a soft gelatin capsule, asyrup or a liquid suspension. Creams, gels, and salves may be preparedin conventional manners for topical administration and suppositories maybe prepared for rectal administration.

The active compounds of formula I and of the compositions of thisinvention are present in an amount sufficient to treat inflammation,that is to reduce inflammation. Advantageously, the composition willcontain the active ingredient, namely, the compounds of formula I in anamount of from about 1 to 140 mg. per day), preferably from about 2 mg.to 70 mg./kg. body weight per day mg. to 5 g. per patient per day).

The method of treatment of this invention comprises internallyadministering to a patient (animal or human), a compound of formula I,particularly an especially preferred compound admixed with a non-toxicpharmaceutical carrier such as exemplified above. The compounds offormula I and particularly the especially preferred compounds will bepresent in an amount of from l mg. to mg./kg. body weight per day,preferably from about 2 mg. to about 70 mg. per kilogram body weight perday and especially from 4 mg. to 10 mg./kg. body weight per day. Themost rapid and effective anti-inflammatory effect is obtained from oraladministration of a daily dosage of from about 4 to 10 mg./kg./day. Itshould be understood, however, that although preferred dosage ranges aregiven, the dose level for any particular patient depends upon theactivity of the specific compound employed. Also many other factors thatmodify the actions of drugs will be taken into account by those skilledin the art in the therapeutic use of medicinal agents, particularlythose of formula I, for example, age, body weight, sex, time ofadministration, route of administration, rate of excretion, drugcombination, reaction sensitivities and severity of the particulardisease.

The compounds of this invention may be prepared either from a biphenylphenol or from the following type starting material:

wherein:

A is an alkali metal ion; and

X, R and R are as previously defined.

Some of these compounds are prepared from the individual phenyl moietiesof the above starting material by the wellknown Gomberg reaction.Others, where the biphenyl moiety is known, require the appropriatereactions to obtain the functional group, if needed, as well as themetal salts. However, all of the compounds may be obtained by firstpreparing an aniline compound containing an X. and, if desired, an Rgroup, followed by a Gomberg reaction with nitrobenzene or anisole or anR substituted nitrobenzene or anisole, subsequently reacting either thenitro group or the methoxy group (from nitrobenzene or anisole) of thebiphenyl compound thus prepared so as to obtain the alkali salt startingmaterial. For example, 2-f1uoro-5-nitroaniline may be diazotized to thecorresponding 2-fluoro-5-nitrophenol which in turn may be alkylated toform the corresponding 3-alkoxy-4- fluoronitrobenzene, and finallyreducing the nitro group to obtain the appropriate aniline compoundneeded for the Gomberg reaction. (When as in this cited example, thebenzene compound contains an alkoxy group, the Gomberg reaction iscarried out with nitrobenzene). The methoxy substituted aniline compoundis then reacted with nitrobenzene in the presence of isoamyl nitrite.The nitrobiphenyl compound thus obtained may be readily reduced to theamino compound and subsequently diazotized to the corresponding hydroxycompound. Alternatively, when the aniline compound used in the Gombergreaction does not have an alkoxy substituent on it, it may be reactedwith an alkoxy benzene rather than nitrobenzene. Using this procedure,the alkoxy biphenyl compound obtained after the Gomberg reaction may, byone step, be converted to the corresponding hydroxy-biphenyl compound,for example, by reaction with hydriodic acid.

Although the above reaction sequence can be used when R is methyl, it ispreferred to carry out the following reaction sequence when R is loweralkyl: For example, the methyl-2- hydroxy-5-(4-fluorophenyl)-benzoatecompound of this invention is reduced to the corresponding alcohol. Thisalcohol compound is then acylated, whereupon it is subsequentlyhydrogenated to the corresponding 4-(4'-fluorophenyl)-2- methylphenylacetate. This compound is then saponified or hydrolyzed to thecorresponding phenol compound, which in turn is carbonated to form the5-(4'-flu0rophenyl)-2-l1ydroxy- 3-methyl-benzoic acid. Further, when Ris to be a lower alkenyl group, the following procedure is preferred:For example, methyl 5-(4'-fluorophenyl)-2-hydroxy benzoate is heatedwith potassium carbonate in acetone to form the corresponding 2-allyloxy compound. This product is then heated at high temperatures tocause a rearrangement to the corresponding 3- allyl-2-hydroxy compound.Further, an additional method for preparing an R alltyl is by reduction,for example, of the above-noted 3-allyl compound to the corresponding3-propyl compound. In addition, the 3-allyl compound above may be heatedwith potassium hydroxide to obtain a double bond shift to form the3-propenyl compound.

In the Gomberg reaction mentioned above, a mixture of isomers of thebiphenyl compound is obtained; therefore, in order to obtain the desired4(and 5)-(substituted phenyl)- benzene compounds in a pure form achromatographic separation is required.

The (substituted phenyl)-phenol compounds obtained as described abovemay then be converted to the corresponding alkali salt by any well-knownmeans, for example, reaction with an appropriate alkali metal in aninert solvent.

The benzoic acid compounds may be prepared from the previously preparedalkali phenolate or phenol compound. The preparation of these acidcompounds are carried out by using the well-known Kolbe-Schmidtcarbonation procedure. in this carbonation step, the phenolate isreacted with carbon dioxide or the phenol is reacted with carbon dioxidein the presence of an alkali carbonate. Many of the acids which are notclaimed in this invention can be used as starting materials for thenovel esters and amides of this invention. The process may be shown asfollows:

Equivalents: As previously indicated. Reactions and Conditions:

Step 1. Reaction with carbon dioxide at elevated temperatures (above C.preferably above C.) with or without a solvent preferably without asolvent (or if the solvent is used, any highboiling inert solvent may beused) until the reaction is substantially complete; and subsequentacidification of the mixture.

Step 2. Reaction with carbon dioxide in the presence of an alkalicarbonate, such as potassium, sodium and the like, especially potassium,at elevated temperatures (above 75 C. preferably above 100 C.) with orwithout a solvent preferably without a solvent (or if the solvent isused, any high-boiling inert solvent may be used) until the reaction issubstantially complete; and subsequent acidification of the reactionmixture.

Reaction steps 1 and 2 are the well-known lKolbe-Schmidt reaction. Sincethe reaction conditions are not critical, this invention contemplatesnot only the particular procedure shown but all other variations of thiscarbonation step which are well known in the art.

The phenylacetic acid compounds of this invention may be prepared byreacting the corresponding hydroxy benzoic acid with a lower alkanoicacid anhydride (preferably acetic anhydride) in the presence of acatalyst, such as sulfuric acid, pyridine, p-toluenesulfonic acid andthe like (preferably pyridine), at any suitable temperature from roomtemperature to elevated temperatures (preferably at elevatedtemperatures) to form the desired R compound which then undergoes theArndt-Erstert synthesis to form the desired acetic acid compound. Thissynthesis involves three steps:

1. formation of the acid chloride by reacting the benzoic acid with anysuitable chloride of the formula SOCI POCl or R-COCl wherein R alkyl,aryl or heteroaryl;

2. reaction of the acid chloride with diazomethane to form adiazoketone; and

3. rearrangement of the diazoketone, with loss of nitrogen, in thepresence of a catalyst (silver, platinum, copper). An acid is formed inthe presence of water, an ester is produced in an alcohol, and an amideresults when ammonia is used.

The compounds of this invention, wherein R is a group such that an esteris the final compound, (i.e. R alltoxy), are prepared by anyesterification procedure, using an esterifying agent containing theappropriate R, group. For example, the

phenylacetic acid compounds of this invention may be reacted with theappropriate lower alkanol (preferably methanol) at elevated temperaturesin the presence of a strong acid, such as hydrochloric acid, sulfuricacid, p-toluenesulfonic acid, and the like, to form the desired R,compound.

The compounds of this invention, wherein R, is a group such that anamide is the final compound (i.e., R, is amino), may also be present byany suitable amidation reaction. For example, the phenylacetic acidcompound (preferably the methyl or ethyl ester) may be reacted withammonia, ammonium hydroxide, or an amine compound, at any suitabletemperature (room temperature to reflux). When the amino group isdesired, it is preferred to carry out the reaction with ammonia in abomb at temperatures above 100 C. to form the desired R, (amino)compound. Preferably, when an amide is desired which is derived from anamino acid, the following reaction sequence is followed: Thephenylacetic acid final compound is reacted with isobutylchlorocarbonate to form the mixed anhydride. This compound is in turnreacted when the desired amino acid ester and subsequently hydrolyzed toform the desired amide.

The final compound, wherein R is lower alkanoyl (preferably acetyl), maybe prepared by any suitable alkanoylation reaction. For example, thecorresponding hydroxy phenylacetic acid, ester or amide (preferably theester), may be reacted with a lower alkanoic acid anhydride (preferablyacetic anhydride) in the presence of a catalyst, such as sulfuric acid,pyridine, p-toluenesulfonic acid, and the like (preferably pyridine), atany suitable temperature (room temperature to elevated temperatures)preferably at elevated temperatures to form the desired R compound.

The final compound, wherein R is lower alkyl (preferably methyl), may beprepared by any appropriate alkylation reaction. For example, thecorresponding hydroxy phenylacetic acid, ester, or amide (preferably theester), may be reacted with a di(lower alkyl)sulfate (preferablydimethyl sulfate) in the presence of a base (such as an alkalicarbonate) at any suitable temperature (room temperature to reflux butpreferably at or near reflux) with subsequent acidification of thereaction mixture, such as with hydrochloric acid, sulfuric acid, and thelike, to form the desired R compound.

The final compound, wherein R is a lower alkenyl (preferably allyl), mayalso be prepared by any appropriate alkylation reaction. For example,the hydroxy phenylacetic acid, ester, or amide (preferably the ester),may be reacted with an alkenyl halide in the presence of a basecontaining an inorganic cation, such as sodium methoxide, potassiumethoxide, sodium carbonate, and the like, in an inert solvent whichaffords at least some solubilization [such as dioxane, tetrafuran, loweralkanol, dimethoxy ethane, acetone, and the like (preferably a loweralkanol, such as methanol)] at any suitable temperature (roomtemperature to elevated temperatures, preferably at elevatedtemperatures) to form the desired R compound.

The salts of the final acid compounds of this invention may be preparedby any of the well-known metathesis procedures. For example, thephenylacetic acid compound may be reacted with an inorganic base, suchas sodium hydroxide, potassium hydroxide, ammonium hydroxide, bariumhydroxide, and the like. The anhydrides of this invention may beprepared by any of the well-known procedures in the art.

The preparation of these compounds containing the R, and R groups otherthan hydrogen may be prepared in any order. The R, group could be placedon the molecule followed by addition of the R substituent or by firstobtaining the R compound followed by addition of the R, group. The orderof these reactions is not critical; they can be run in any desiredfashion.

The following examples are used by way of illustration:

EXAMPLE l 4-( 4'-Fluorophenyl)aniline A solution of 3 g.4'-fluoro-4-nitrobiphenyl in 125 ml. methanol is reduced by hydrogen atroom temperature and 40 p.s.i. pressure using mg. platinum oxidecatalyst. After the required uptake of hydrogen, the mixture isfiltered, 50 ml. 2.5 N hydrochloric acid added and the resultingsolution is evaporated in vacuo. After washing the residue with ether,it is dissolved in methanol, filtered and diluted with excess ether. Theprecipitate which is 4-(4'-fluorophenyl)aniline hydrochloride isfiltered, washed with ether and dried in vacuo at room temperature.

EXAMPLE 2 A mixture of 7.5 g. of pentafluoroauiline, 200 ml. ofnitrobenzene, and 9.0 g. of iso-amyl nitrite, is warmed on the steambath until a vigorous reaction with evolution of gas sets in. Thisevolution is allowed to proceed without heating until it has subsided,and the mixture is then heated on the steam bath for an additional 3hours. The excess of nitrobenzene is removed in vacuo. The residue ispurified for the desired isomer by elution from a silica gel columnusing petroleumbenzene to yield 2',3',4',5,6'4-nitrobiphenyl and2',3',4',5 ,6'-pentafluoro-3-nitrobiphenyl.

When Z-fluoroaniline is used in place of pentafluoroaniline in the aboveexample, there is obtained 2'-fluoro-4- nitrobiphenyl and2'-fluoro-3-nitrobiphenyl.

When 2-nitrotoluene, 2-ethyl-nitrobenzene, 2-methoxynitrobenzene,Z-ethoxy-nitrobenzene, 2-chloro-nitrobenzene, 2-bromo-nitrobenzene,3-nitrotoluene, 3-ethylnitrobenzene, S-methoxy-nitrobenzene,3-ethoxy-nitrobenzene, 3-chloronitrobenzene, or 3-bromo-nitrobenzene areused in place of nitrobenzene in the above example, there is obtainedthe corresponding 2- and 3-alkyl, halo or alkoxy biphenyls.

When 4-fluoroaniline and Z-methyl-nitrobenzene are used in the aboveexample in place of 4-fluoro-2-methoxyaniline and nitrobenzene there isobtained 4'-fluoro-3-methyl-4- nitrobiphenyl and4-fluoro-4-methyl-3-nitrobiphenyl.

EXAMPLE 3 4-(Pentafluorophenyl)-aniline A mixture of 5 g. of2',3,4',5',64- nitrobiphenyl in 250 ml. of ethanol is reduced byhydrogen at atmospheric pressure and at room temperature using 5 percentpalladium-on-charcoal (0.5 g.) catalyst. After the required uptake ofhydrogen, the mixture is filtered and the catalyst washed with freshethanol. The ethanol solution is then concentrated in vacuo, and theresidue recrystallized from aqueous ethanol to yield4-(pentafluorophenyl)aniline.

When 2'-fluoro4-nitrobiphenyl is used in place of 2',3,4',5,6-pentafluoro-4-nitrobiphenyl in the above examples, there isobtaihed4 0-fluorophenyl)-aniline.

When 2'-fluoro-3-nitrobiphenyl is used in place of 2'-fluoro-4-nitrobiphenyl according to the above procedure, there isobtained 3 -(2-fluorophenyl)-aniline.

Similarly, when 4-fluoro-2-methyl-3-nitrobiphenyl obtained from Example2 is used in place of 2',3,4,5,6- pentafluoro-4-nitrobiphenyl in theabove example, there is obtained 2-methyl-3-(4-fluorophenyl)-aniline.

When the 2- and 3-alkyl, halo or alkoxy biphenyls obtained from Example2 are used in place of 4' fluoro-2-methoxy-4- nitrobiphenyl in the aboveexample, there are obtained the corresponding 2- or 3-alkyl, halo oralkoxy aniline compounds.

EXAMPLE 4 3-(3'-Chloro-4-fluorophenyl)-anisole and 4-(3-chloro-4-fluorophenyI)-anisole A mixture of 8.0 g. of 3-chloro-4-fluoroaniline,200 ml. of anisole, and 9.0 grams of iso-amylnitrite, is warmed on asteam bath until a vigorous reaction with evolution of gas sets in. Thisevolution is allowed to proceed without heating until it has subsided,and the mixture is then heated until it has subsided, and the mixture isthen heated on the steam bath for an additional 3 hours. The excessanisole is removed in vacuo, and the residue is chromatographed on asilica gel column using petroleum-benzene as eluent to yield3-(3'-chloro-4- fluorophenyl)-anisole and 4-(3'-chloro-4-fluorophenyl)-anisole.

When 2-chloro-4-fluoroaniline, 2,4-difluoroaniline and 3- fluoroanilineare used in place of 3-chloro-4-fluoroaniline in the above example,there are obtained the corresponding 3(and4)-(2'-chloro-4'-fluorophenyl)-anisole, 3(and 4)-(2,4'-difluorophenyl)-anisole and 3(and 4)-(3'-fluorophenyl)- anisole.

When 2-methylanisole, Z-ethylanisole, Z-benzylanisole, 3- methylanisole,3-ethylanisole, 3-benzylanisole, 2- chloroanisole, 2-bromoanisole,3-chloroanisole or 3- bromoanisole is used in place of anisole in theabove example, there is obtained the corresponding 2- or 3- alkyl,benzyl or halo substituted biphenyl compound.

EXAMPLE 5 4 3 '-Chloro-4'-fluorophenyl )-phenol To a solution of 2.1 g.of 4-(3'-chloro-4'-fluorophenyl)- anisole in 50 ml. of boiling aceticacid is added 5 ml. of hydriodic acid and the boiling continued for 3hours. Water is added and the reaction mixture cooled and the4-(3'-chloro- 4'-fluorophenyl)-phenol crystallizes. Further purificationis then achieved by recrystallization of the solid from aqueous ethanolto yield 4-( 3 '-chloro-4'-fluorophenyl )-phenol.

When 4-(2'-chloro-4'-fluorophenyl)-anisole, 3-(2,4-difluorophenyl)-anisole and 4(3-fluorophenyl)-anisole obtained fromExample 4 are used in place of 4-(3-chl0ro-4- fluorophenyl)-anisole inthe above example, there are obtained the corresponding4-(2'-ch1oro-4'-fluorophenyl)- phenol, 3-(2',4'-dif1uorophenyl)-phenoland 4-(3'- fluorophenyl)-phenol.

When the 2- or 3-alkyl, benzyl or halo substituted biphenyl compoundsobtained from Example 4 above are used in place of4-(3'-chloro-4'-fluorophenyl)-anisole in the above example, there isobtained the corresponding 4-(substituted phenyl)-2- or 3-alkyl, benzylor halo phenol compound.

EXAMPLE 6 4-(4'-Fluorophenyl)-phenol A solution of 32.66 g. of4-(4'-fluorophenyl)-aniline in 120 ml. of glacial acetic acid is cooledto l-l2 C. To this solution is added slowly a solution of 12.25 grams ofsodium nitrite in 120 ml. of water with stirring and continued cooling.Five minutes after this addition, the suspension of the diazoniumacetate is added slowly to a boiling solution of 100 ml. of concentratedsulfuric acid and 200 ml. of water. After the final addition of thediazonium salt, the suspension is boiled for an additional minutes andthen allowed to cool to room temperature. The reaction mixture is thenfiltered and the cake dried in vacuo to yield4-(4'-fluorophenyl)-phenol, (m.p. l52l6l C., 24.07 g.).

When 4-( 2'-fluorophenyl )-aniline, 3 -(pentafluorophenyl)- aniline, and3-(4'-fluoro-3'-methoxyphenyl)-aniline, obtained from Example 3 are usedin place of 4-(4'-fluoro-2'-mcthoxyphenyl)-aniline in the above example,there are obtained the corresponding 4-(2'-fluorophenyl)-phenol,3-(pentfluorophenyl)phenol, and 3-(4'-fluoro-3'-methoxyphenyl)- phenol.

When the alkyl, halo or alkoxy aniline compounds obtained from Example 3are used in place of 4-(4-fluorophenyl)- aniline in the above example,there is obtained the corresponding 2- or 3-alkyl, halo or alkoxy phenolcompound.

Similarly, when 2-methyl-4-(4-fluorophenyl)-aniline obtained fromExample 3 is used in place of -(4'-fluorophenyl)- aniline in the aboveexample, there is obtained 2-methyl4-(4 -fluorophenyl )-phenol.

EXAMPLE 7 2-Hydroxy-5-( 4'-f1uorophenyl )-benzoic acid A mixture of 10g. of 4'(4'-fluorophenyl)-phenol and 27.2 g. of potassium carbonate isexposed to carbon dioxide at 1,300 p.s.i. and 175 C. The dark massobtained from this carbonation is dissolved in 300 ml. of water and 200ml. of methylene chloride and the two layers separated. The water layeris extracted with ml. of methylene chloride and then acidified with 2.5normal hydrochloric acid. This mixture is filtered and the cake dried invacuo to yield 5.32 g. of the crude product. The crude product isrecrystallized from benzene-methanol to yield 2.7 grams of material(m.p. 200204 C. An additional crystallization of this semi-pure materialfrom benzene-methanol yields analytically pure 2-hydroxy-5-(4-fluorophenyl)-benzoic acid (m.p. l99203 C.).

4'-fluorophenyl)-phenol, 4-(2',4-difluorophenyl)-phenol and 4-(35 and 4-(2-fluorophenyl)-phenol and 4-(pentafluorophenyl)'phenol obtained fromExample 6 are used in place of 4(4'- fluorophenyl)-phenol in the aboveexample, there are obtained the corresponding 2-hydroxy-5(3'-chloro-4'-fluorophenyl )-benzoic acid, 2-hydroxy-5 2 '-chloro-4fluorophenyl)-benzoic acid, 2-hydr0xy-5-(2',4'-difiu0rophenyl)-benzoicacid (m.p. 210-2l 1 C.), 2-hydroxy-5-(3'- fluorophenyl)-benzoic acid(m.p. l96l 97 C. 2-hydroxy-5- (2'-fluorophenyl)-benzoic acid (m.p.201203 C.) and 2- hydroxy-S-(pentafluorophenyl)-benzoic acid (m.p.241-243 C.).

When the 3(or 4)-(substituted-pheny1) 2- or 3-alkyl, benzyl or halophenol compounds of Example 5 or the 2 or 3-alkyl, halo or alkoxy phenolcompounds of Example 6 are used in place of4-(4-fluoro-2-methoxy-phenyl)-phenol in the above, there are obtained2-hydroxy-3-methyl-4(and 5)-(4'- fluoro-2-methoxyphenyl)-benzoic acid,2-hydroxy-3-ethyl-4 (and 5)-(4flu0ro-2'methoxyphenyl)-benzoic acid,2-hydroxy-3-methoxy-4(and 5 )-(4-fiuoro-2-me}hoxyphenyl )-benzoic acid,2-hydroxy-3-3-ethoxy-4(and 5)-(4'-fluoro-2-methox yphenyl)-benzoic acid,2-hydroxy-3-chloro-4(and 5)-(4- fluoro-2'-methoxyphenyl)-benzoic acid,2-hydroxy-3-bromo- 4(and 5)-(4'-fluoro-2-methoxyphenyl)-benzoic acid, 2-hydroxy-4-methyl-5-( 4'-fluoro-2-methoxyphenyl )-benzoic acid,2-hydroxy-4-ethyl-5-( 4-fluoro-2 '-methoxyphenyl benzoic acid,2-hydroxy-4-methoxy-5-(4-fluoro'2'-methoxyphenyl)-benzoic acid,2-hydroxy-4-ethoxy-5-(4'-fiuoro- 2- methoxyphenyl)-benzoic acid,2-hydroxy-4-chloro-5(4'- fluoro-2'methoxyphenyl)-benzoic acid,2-hydroxy-4- bromo- 5-(4-fluoro-2'-methoxyphenyl)-benzoic acid,2-hydroxy-3- methyl-4(and 5 3'-chloro-4'-fluorophenyl)-benzoic acid, 2-hydroxy-3-ethyl-4( and 5 3 -chloro-4'-flu0rophenyl )-benzoic acid,2-hydroxy-3-benzyl-4(and 5 3 -chl0ro-4- fluorophenyl)-benzoic acid,2-hydroxy-3-chloro-4(and 5 3' chloro-4-fluorophenyl)-benzoic acid,2-hydroxy-3-bromo-4 (and 5)-(3-chloro-4-fiuorophenyl)-benzoic acid,Z-hydroxy- 3-chloro-4(and 5)-(3'-chloro4'-fluorophenyl)-benzoic acid,2-hydroxy-3-bromo-4( and 5 3 -chloro4 '-fluoro-phenylbenzoic acid,2-hydroxy-4-methyl-5-(2-ch]oro-4'- fluorophenyl)-benzoic acid,2-hydroxy-4-ethyl-5-(2-chloro-4 '-fluorophenyl)-benzoic acid,2-hydroxy-4-benzyl-5-(2'- chloro-4'-flu0rophenyl)-benzoic acid,2-hydroxy-4-chloro-5- (2'-chloro-4-fluorophenyl)-benzoic acid, and2-hyclroxy4- bromo-5-( 2'-chloro4'-fluorophenyl)-benzoic acid,respectively.

Similarly, when 2-methyl-4-(4-fluorophenyl)-phenol obtained from Example6 is used in place of 4-(4'-fluorophenyl)- phenol in the above example,there is obtained 2-hydroxy-5(4 '-fluorophenyl )-3-methyl-benzoic acid.

EXAMPLE 8 2-Acetoxy-5-( 4-fluorophenyl )-benzoic acid A solution of 3.0g. of 2-hydroxy-5-(4'-fluorophenyl)- benzoic acid in 12 ml. of pyridineand 8 ml. of acetic anhydride is heated on a steam bath for 20 minutes.The mixture is then poured onto ice and the product extracted withmethylene chloride. The methylene chloride solution is dried and thenevaporated. The residue is recrystallized from benzene to yield2-acetoxy-5-(4'-fluorophenyl)-benzoic acid (m.p. l34-137C.).

When the Z-hydroxy-benzoic acid compounds obtained from Example 7 areused in place of 2-hydroxy-5-(4- fluorophenyl)-benzoic acid in the aboveexample, there are obtained the corresponding Z-acetoxy-benzoic acidcompounds.

Similarly, when propionic acid anhydride is used in place of aceticanhydride, the corresponding 2-propionoxy compound is obtained.

EXAMPLE 9 2-Acetoxy-5-(p-fluorophenyl)-benzoyl chloride A mixture of 4.3g. of 2-acetoxy-5-(p-fluorophenyl)-benzoic acid and 40 ml. of thionylchloride is refluxed for 30 minutes on the steam bath. The reactionmixture is concentrated in vacuo, 50 ml. benzene added and this solutionreconcentrated in vacuo. The resulting oil is dried under vacuum to give4.4 gm. of 2-acetoxy-5-(p-fluorophenyl-benzoyl chloride.

When the 2-acetoxy-4(or 5)-(phenyl)-benzoic acids of Example 8 are usedin the above procedure the corresponding benzoyl chloride is obtained.

EXAMPLE l 4-Acetoxy-3-diazomethylcarbonyl-4'-fluorobiphenyl A solutionof 4.4 g. of 2-acetoxy-5-(p-fluoropheny1)- benzoyl chloride in 40 ml. ofdry ether is added slowly to the diazomethane prepared from 7.0 g. ofN-nitrosomethylurea and contained in 350 ml. ether. The reaction mixturegradually becomes cloudy and is allowed to stir overnight at roomtemperature. The mixture is then concentrated to half volume, cooled andthe precipitate collected to give 2.4 g. of4-acetoxy-3-diazomethylcarbonyl-4'-fluorobiphenyl in two crops.

When any of the benzoyl chlorides of Example 9 are utilized in the aboveprocedure the corresponding diazoketone is obtained.

EXAMPLE ll -(p-Fluorophenyl)-2-hydroxyphenylacetic acid A solution of2.4 g. of 4-acetoxy-3-diazomethylcarbonyl-4'- fluorobiphenyl in 25 ml.of warm dioxane is added slowly to a mixture of 100 ml. water, 0.8 g. ofsilver oxide, 1.6. g. potassium carbonate and 0.8 g. of sodiumthiosulfate which has been heated to 65-70. The mixture is kept at 65-70for 30 minutes after the addition is complete and then refluxed for 1-2minutes. The reaction mixture is filtered while hot, cooled andacidified with concentrated nitric acid. The precipitate is filtered andair dried to give 829 mg. of crude product. Recrystallization fromtoluene gives 0.54 g. of pure 5-(pfluorophenyl)-2-hydroxyphenyl aceticacid.

When any of the diazoketones produced by the procedure of example 10 areutilized by the above procedure, there is obtained the corresponding4(or 5)-pheny1-2-hydroxyphenyl acetic acid.

EXAMPLE l2 Sodium-2-hydroxy-5-(4'-fluorophenyl)-pheny1acetate A mixtureof 0.1 mole of 2-hydroxy-5-(4'-fluoropheny1)- phenylacetic acid and 0.1mole of sodium hydroxide in 100 ml. of water is stirred at roomtemperature for one-half hour. The reaction mixture is then concentratedin vacuo to yield sodium-2-hydroxy-5-(4'-fluorophenyl)-phenylacetate.

When the phenylacetic acid compounds obtained from Example 1 1 are usedin place of the 2-hydroxy-5-(4'-fluorophenyl)-phenylacetic acid in theabove example, there are obtained the corresponding sodium salts.

Similarly, when choline, glucosamine, S-methylmethionine, potassiumhydroxide, ammonium hydroxide, barium hydroxide, calcium hydroxide,piperazine, chloroquine, hydroxychloroquine, dimethylaminoethanol, andmagnesium hydroxide, are used in place of sodium hydroxide in the aboveexample, there are obtained the corresponding choline, glucoasmine,S-methyl-methionine, potassium, ammonium, barium, calcium, piperazine,chloroquine, hydroxychloroquine, dimethylaminoethanol and magnesiumsalts, respectively.

EXAMPLE 13 A. Methyl-2-hydroxy-5-(4-fluorophenyl )-phenylacetate Asolution of 0.01 mole of 2-hydroxy-5-(4'-fluorophenyl)- phenylaceticacid in 20 ml. of methanol and 2 ml. of concentrated sulfuric acid isheated at reflux for 5 hours. The mixture is then cooled and partitionedbetween (75:150 ml.) water and ethyl acetate and the organic layerwashed with dilute sodium bicarbonate solution. The organic layer isthen dried over magnesium sulfate and concentrated in vacuo to yieldmethy1-2-hydroxy-5-(4-fluorophenyl)-phenylacetate.

When the phenylacetic acid compounds obtained from Example 11 are usedin place of 2-hydroxy-5-(4'-fluorophenyl)- phenylacetic acid in theabove example, there are obtained the corresponding methyl esters.

Similarly, when ethanol and n-butanol are used in place of methanol inthe above example, there are obtained the corresponding ethyl andn-butyl esters.

B. Phenyl 2-hydroxy-5-(4'-fluorophenyl)-phenylacetate A mixture of 0.01mole of 2-hydroxy-5-(4'-fluorophenyl)- phenylacetic acid, 2.8 g. ofphenol and 1.7 g. of phosphorus oxychloride is heated at 114 C. until nomore hydrogen chloride is evolved. The reaction mixture is cooled toroom temperature and filtered. The resulting solid material is digestedin dilute sodium carbonate solution, filtered, washed with water, driedand recrystallized from isopropyl alcohol to yield phenyl2-hydroxy-5-(4'-fluoropheny1)-phenylacetate.

Following the above procedure but using an equivalent amount of2-acetoxy-5-(4'-fluorophenyl)-phenylacetic acid in place of2-hydroxy-5(4'-fluorophenyl)-phenylacetic acid, there is obtained phenyl2-acetoxy-5-(4'-fluorophenyl)-phenylacetate.

C. B-Diethylaminoethyl 2-hydroxy-5-(4'-fluorophenyl)-phenylacetatehydrochloride A mixture of (0.0175 mole) of2-hydroxy-5-(4-fluorophenyl)-pheny1acetic acid, 2.4 g. of potassiumcarbonate in 50 ml. of isopropanol is refluxed for one-half hour 3.0 g.(0.0175 m.) of B-diethylaminoethylchloride. HCl is added and the mixturerefluxed with stirring for 15 hours. The reaction mixture is thendistributed between water and ethyl ether. The ether layer is thenwashed with water, dried and evaporated to a small volume. Dry hydrogenchloride gas is then passed into the ether solution and the resultingprecipitate is filtered and recrystallized from acetone/ethyl ether toyield [3- diethylaminoethyl 2-hydroxy-5-(4'-fluoropheny1)-phenylacetatehydrochloride.

EXAMPLE l4 N,N-Dimethyl-2-hydroxy-5-(4-fluorophenyl)-phenylacetamide Amixture of 0.01 mole of methyl-2-hydroxy-5-(4'-fluorophenyl)-pheny1acetate and 20 ml. of dimethylamine is reacted in abomb at C. for 4 hours. After cooling, the bomb is opened and the excessdimethylamine removed. The residue is then recrystallized from benzeneto yield N,N- dimethyl-2-hydroxy-5-(4'-fluorophenyl)-phenylacetamide.

When the phenylacetic acid methyl esters obtained from Example 13 areused in place of methyl-2-hydroxy-5-(4'- fluorophenyl)-benzoate in theabove example, there are obtained the correspondingN,N-dimethyl-benzamide compounds.

EXAMPLEIS Anhydride of 2-acetoxy-4-(4-fluorophenyl)-phenylacetic acid Asolution of 0.0l mole of 2-acetoxy-4(4'-fluorophenyl)- phenylacetic acidand 0.01 mole of thionyl chloride in 30 ml; of dry benzene is warmeduntil the formation of the substituted benzoyl chloride is complete. Theresulting solution is concentrated to one-half volume in vacuo and isadded to a solution of 0.01 mole of2-acetoxy-4-(4'-fluorophenyl)-phenylacetic acid and 0.01 mole ofpyridine in 30 ml. of benzene. The mixture is stirred at roomtemperature overnight, filtered, and the filtrate washed with colddilute sodium bicarbonate solution. After drying and removal of benzene,the product is recrystallized from benzene-hexane.

Alternatively, the anhydride may be formed by reacting for hours at roomtemperature 0.02 mole of 2-acetoxy-4-(4- fluorophenyl)-phenylacetic acidand 0.01 mole of dicyclohexylcarbodiimide in 20 parts oftetrahydrofuran, followed by filtration and concentration of thefiltrate to yield the anhydride.

When a solution of 2-acetoxy phenylacetic acid in pyridine is used inplace of the 2-acetoxy-4-(4'-fluorophenyl)-phenylacetic acid pyridinesolution in the above example, there is obtained the mixture anhydrideof 2-acetoxy-4-(4'- fluorophenyl)-phenylacetic acid and 2-acetoxyphenylacetic acid.

EXAMPLE 16 A dry filled capsule is prepared from the followingcomponents:

Z-acetoxy- 5(4'-fluorophenyl)phenylacetic acid 300 mg. corn starch 150mg. Cab-o-sil 5 mg. Sterotix mg.

A dry filled capsule can be prepared by using the following compounds asactive ingredients instead of 2-acetoxy-5-(4- fluorophenyl)-phenylaceticacid:

2-hydroxy-4(0r 5 )-(4-fluorophenyl)-phenylacetic acid;

2-acetoxy-4(or 5 )-(2',4'-difluorophenyl)-phenylacetic acid;2-hydroxy-3-methyl-4(or ylacetic acid;

phenyl 4(or 5 )-(4'-fluorophenyl)-2-hydroxy phenylacetate;

2-hydroxy-4(or 5 3 -fluorophenyl)-phenylacetic acid; or any otherpreferred compounds as shown in the specification.

lf capsules of lower potency are to be made, the capsule size could bereduced or the quantity of corn starch could be increased.

EXAMPLE 1? Compressed tablets are prepared with the followingcomponents:

Z-acetoxy- 5 (4"fluorophenyl)-phenylacetic acid 300 mg. cornstarch 30mg. polyvinylpyrrolidone 10 mg; magnesium stearate 3 mg.

tablet size as necessary.

We claim:

1. A compound of the formula:

or a pharmaceutically non-toxic acid addition salt thereof, wherein X ischloro or fluoro;

R is hydrogen, loweralkyl or lower alkoxy;

R is hydroxy or lower alkoxy;

R is hydrogen or lower alkanoyl;

R is loweralkyl or hydrogen.

2. A compound of the formula:

CHz-C-OH R or a pharmaceutically non-toxic acid addition salt thereof,wherein:

R is methyl or methoxy;

R is hydrogen or acetyl;

R is hydrogen or methyl.

3. 2-Hydroxy-5-(4'-fluorophenyl)-phenylacetic acid.

4. 2-Hydroxy-4-(4'-fluorophenyl)-phenylacetic acid.

2. A compound of the formula: 3.2-Hydroxy-5-(4''-fluorophenyl)-phenylacetic acid. 4.2-Hydroxy-4-(4''-fluorophenyl)-phenylacetic acid.